Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form

Abstract

Accelerated atherosclerosis is the primary cardiovascular manifestation of diabetes and correlates inversely with levels of circulating adiponectin, an anti-atherosclerotic adipokine that declines in diabetes. We therefore initiated a study to examine the mechanisms by which adiponectin, a hormone released from adipose tissue, influences the proliferation of vascular smooth muscle cells (SMCs). Addition of adiponectin to quiescent porcine coronary artery SMCs increased both protein and DNA synthesis and concurrently activated ERK1/2 and Akt. By contrast, globular adiponectin, a truncated form of this protein, exhibited anti-mitogenic properties as indicated by the inhibition of protein and DNA synthesis in SMCs stimulated with platelet-derived growth factor (PDGF). Whereas globular adiponectin did not stimulate growth-related signal transduction pathways, it was able to block the PDGF-dependent phosphorylation of eukaryotic elongation factor 2 kinase, a regulator of protein synthesis. Proteolysis of adiponectin with trypsin, which produces globular adiponectin, reversed the growth-stimulating actions of the undigested protein. As the existence of globular adiponectin remains controversial, western blotting was used to establish its presence in rat serum. We found that globular adiponectin was detectable in rat serum, but this result was not obtained with all antibodies. The contrasting properties of adiponectin and its globular form with respect to SMC proliferation suggest that protection against atherosclerosis may therefore be mediated, in part, by the level of globular adiponectin.

Gender-Specific Associations between Circulating T-Cadherin and High Molecular Weight-Adiponectin in Patients with Stable Coronary Artery Disease

“…Moreover, levels of T-cad were much less abundant in the secretome from diabetes-susceptible mice [42], which is concordant with the previous finding of lower levels of T-cad in diabetic patients as compared to patients without diabetes [19]. Circulating APN is predominantly derived from adipocytes but several other cell types including cardiomyocytes [43], SMC [44] and EC [8,45] can also synthesize and secrete APN. T-cad is expressed on the surface of these cell types [46–48] and therefore locally produced APN together with circulating adipocyte-derived APN may have important autocrine mechanisms of action.…”

AdipoRon, an adiponectin receptor agonist, attenuates PDGF-induced VSMC proliferation through inhibition of mTOR signaling independent of AMPK: Implications toward suppression of neointimal hyperplasia

“…In addition, adiponectin attenuates IGF1-induced ERK phosphorylation in rat aortic VSMCs [34]. However, in a different study, adiponectin induces ERK phosphorylation in porcine coronary artery VSMCs [42]. In the present study, AdipoRon treatment between 6 min and 48 hr does not affect the basal phosphorylation of C-Raf and MEK, the kinases upstream of ERK.…”

Adiponectin, Leptin, and Resistin in Asthma: Basic Mechanisms through Population Studies

“…Adiponectin also reduces the platelet-derived growth factor (PDGF) or serotonin induced proliferation of murine airway smooth muscle cells in culture (unpublished observations), consistent with its inhibitory effects on vascular smooth muscle proliferation [ 35 ]. Interestingly, in rat vascular smooth muscle, the antiproliferative effects of adiponectin are observed with the globular but not the full-length isoforms, suggesting that proteolytic cleavage of this adipokine is required for its biological effects on smooth muscle [ 48 ].…”